346 research outputs found
Formulations for Allergen Immunotherapy in Human and Veterinary Patients: New Candidates on the Horizon
Allergen immunotherapy is currently the only causal treatment for allergic diseases in human beings and animals. It aims to re-direct the immune system into a tolerogenic or desensitized state. Requirements include clinical efficacy, safety, and schedules optimizing patient or owner compliance. To achieve these goals, specific allergens can be formulated with adjuvants that prolong tissue deposition and support uptake by antigen presenting cells, and/or provide a beneficial immunomodulatory action. Here, we depict adjuvant formulations being investigated for human and veterinary allergen immunotherapy
A comparative approach of tumor associated inflammation in mammary cancer between humans and dogs
Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seems to exhibit exclusive phenotypic and functional characteristics and mammary cancer
cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory
cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor growth factor EGF, the angiogenic growth factor VEGF, other proangiogenic factors and a large variety of chemokines and cytokines that amplify the inflammatory state.
This review describes the intertwined signaling pathways shared by Tlymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis.The work was supported partially by the Strategic Research project Pest-OE/AGR/UI0772/2011 and the Research Project UID/AGR/04033/2013, by a Ph.D. scholarship SFRH/BD/ 78771/2011 financed by the Portuguese Foundation for Science and Technology (FCT), and in part by the Austrian Science Fund (FWF), SFB F4606-B28, to Erika Jensen Jarolim
Aging (Albany NY)
The combination of functional genomics with next generation sequencing facilitates new experimental strategies for addressing complex biological phenomena. Here, we report the identification of a gain-of-function allele of peroxiredoxin (thioredoxin peroxidase, Tsa1p) via whole-genome re-sequencing of a dominantSaccharomyces cerevisiae mutant obtained by chemical mutagenesis. Yeast strain K6001, a screening system for lifespan phenotypes, was treated with ethyl methanesulfonate (EMS). We isolated an oxidative stress-resistant mutant (B7) which transmitted this phenotype in a background-independent, monogenic and dominant way. By massive parallel pyrosequencing, we generated an 38.8 fold whole-genome coverage of the strains, which differed in 12,482 positions from the reference (S288c) genome. Via a subtraction strategy, we could narrow this number to 13 total and 4 missense nucleotide variations that were specific for the mutant. Via expression in wild type backgrounds, we show that one of these mutations, exchanging a residue in the peroxiredoxin Tsa1p, was responsible for the mutant phenotype causing background-independent dominant oxidative stress-resistance. These effects were not provoked by altered Tsa1p levels, nor could they be simulated by deletion, haploinsufficiency or over-expression of the wild-type allele. Furthermore, via both a mother-enrichment technique and a micromanipulation assay, we found a robust premature aging phenotype of this oxidant-resistant strain. Thus, TSA1-B7 encodes for a novel dominant form of peroxiredoxin, and establishes a new connection between oxidative stress and aging. In addition, this study shows that the re-sequencing of entire genomes is becoming a promising alternative for the identification of functional alleles in approaches of classic molecular genetics
Prospective Evaluation of Pregnancy-Associated Plasma Protein-A and Outcomes in Patients With Acute Coronary Syndromes
ObjectivesThis study sought to investigate whether pregnancy-associated plasma protein-A (PAPP-A) is useful for risk assessment in nonâST-segment elevation acute coronary syndrome (NSTE-ACS).BackgroundPAPP-A is a high molecular weight, zinc-binding metalloproteinase that is associated with vulnerable plaque and may be a predictor of cardiovascular disease and mortality.MethodsWe measured PAPP-A at baseline in 3,782 patients with non NSTE-ACS randomized to ranolazine or placebo in the MERLINâTIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) trial and followed for an average of 1 year. A cut point of 6.0 ÎŒIU/ml was chosen from pilot work in this cohort.ResultsPAPP-A >6.0 ÎŒIU/ml at presentation was associated with higher rates of cardiovascular death (CVD) or myocardial infarction (MI) at 30 days (7.4% vs. 3.7%, hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.43 to 2.82; p < 0.001) and at 1 year (14.9% vs. 9.7%, HR: 1.63; 95% CI: 1.29 to 2.05; p < 0.001). PAPP-A was also associated with higher rates of CVD (HR: 1.94; 95% CI: 1.07 to 3.52, p = 0.027) and myocardial infarction (HR: 1.82; 95% CI: 1.22 to 2.71, p = 0.003) individually at 30 days. There was no difference in the risk associated with PAPP-A stratified by baseline cardiac troponin I [Accu-TnI >0.04 ÎŒg/l], p interaction = 0.87). After adjustment for cardiac troponin I, ST-segment deviation, age, sex, diabetes, smoking, hypertension, and coronary artery disease, PAPP-A was independently associated with CVD/myocardial infarction at 30 days (adjusted HR: 1.62, 95% CI: 1.15 to 2.29; p = 0.006) and 1 year (adjusted HR: 1.35, 95% CI: 1.07 to 1.71; p = 0.012). PAPP-A also improved the net reclassification for CVD/MI (p = 0.003). There was no significant interaction with ranolazine.ConclusionsPAPP-A was independently associated with recurrent cardiovascular events in patients with NSTE-ACS. This finding supports PAPP-A as a candidate prognostic marker in patients with ACS and supports investigation of its therapeutic implications
PIPE-cloned human IgE, IgG1 and IgG4 antibodies: New tools for investigating cowâs milk allergy and tolerance
Cow's milk (CM) allergy (CMA) is defined as an immune-mediated adverse response to CM proteins. 2% to 3% of children are suffering from CMA, but many develop natural tolerance after 3-4 years.1,S01 Food allergen immunotherapy (FA-AIT) applying increasing antigen doses (oral immunotherapy, OIT) can contribute to improvement of CMA,S02 with variable clinical efficacy,2,S03 but immunologically often resulting in decreased specific IgE levels and increased specific IgG4 levelsS04,S05. IgG4 is (a) anti-inflammatory as it does not activate the complement system; (b) bi-specific due to fab-arm exchange and, thus, has less crosslinking capacity than IgE, but has (c) blocking capacity.3 The interplay of IgE and IgG4 may hence be decisive for the immune balance in CMA.This work was supported by the Austrian Science Fund (FWF) grants MCCA W1248-B30 and SFB F4606-B28 to EJJ. CP received an EFIS-IL short-term research fellowship for a research visit at Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. The research was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy's and St Thomas' NHS Foundation Trust and King's College London (IS-BRC-1215-20006) (SNK). The authors acknowledge support by the Medical Research Council (MR/L023091/1) (SNK); Breast Cancer Now (147), working in partnership with Walk the Walk (SNK); Cancer Research UK (C30122/A11527; C30122/A15774) (SNK); Cancer Research UK Kingâs Health Partners Centre at Kingâs College London (SNK); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587) (SNK). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Additionally, was this work funded by Instituto de Salud Carlos III through the project "PI16/01223" (Co-funded by European Regional Development Fund; âA way to make Europeâ) to FB and by the Department of Health, Basque Government through the project â2019111031â to OZ. OZ is recipient of a Sara Borrell 2017 postdoctoral contract âCD17/00128â funded by Instituto de Salud Carlos III (Co-funded by European Social Fund; âInvesting in your future")
Comparative oncology: The paradigmatic example of canine and human mast cell neoplasms
In humans, advanced mast cell (MC) neoplasms are rare malignancies with a poor prognosis. Only a few preclinical models are available, and current treatment options are limited. In dogs, MC neoplasms are the most frequent malignant skin tumours. Unlike low-grade MC neoplasms, high-grade MC disorders usually have a poor prognosis with short survival. In both species, neoplastic MCs display activating KIT mutations, which are considered to contribute to disease evolution. Therefore, tyrosine kinase inhibitors against KIT have been developed. Unfortunately, clinical responses are unpredictable and often transient, which remains a clinical challenge in both species. Therefore, current efforts focus on the development of new improved treatment strategies. The field of comparative oncology may assist in these efforts and accelerate human and canine research regarding diagnosis, prognostication, and novel therapies. In this article, we review the current status of comparative oncology approaches and perspectives in the field of MC neoplasms
Major Allergen Content in Allergen Immunotherapy Products: The Limited Value of Numbers
The prevalence of allergic disorders has increased drastically over the last 50 years to the extent that they can be considered epidemic. At present, allergen-specific immunotherapy (AIT) is the only therapy that targets the underlying cause of allergic disorders, and evidence of its superiority is based on data accumulated from clinical trials and observational studies demonstrating efficacy and safety. However, several aspects remain unresolved, such as harmonization and standardization of manufacturing and quantification procedures across manufacturers, homogeneous reporting of strength, and the establishment of international reference standards for many allergens. This article discusses issues related to the measurement of major allergen content in AIT extracts, raising the question of whether comparison of products from different manufacturers is an appropriate basis for selecting a specific AIT product. Allergen standardization in immunotherapy products is critical for ensuring quality and, thereby, safety and efficacy. However, lack of harmonization in manufacturing processes, allergen quantification (methodologies and references), national regulatory differences, clinical practice, and labeling shows that the comparison of AIT products based solely on major allergen amounts is not rational and, in fact, impossible. Moreover, when rating the information given for a specific product, it is necessary to take into account further inherent characteristics of products and their application in clinical practice, such as the state of extract modification, addition of adjuvant or adjuvant system, route of administration (sublingual/ subcutaneous), and cumulative dose as per posology (including the volume per administration). Finally, only convincing clinical data can serve as the basis for product-specific evaluation and cross-product comparability of individual products
Blood group terminology 2004: from the International Society of Blood Transfusion committee on terminology for red cell surface antigens
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73460/1/j.1423-0410.2004.00564.x.pd
B-Type Natriuretic Peptide and Cardiac Troponin I Are Associated With Adverse Outcomes in Stable Kidney Transplant Recipients
Approximately 200,000 kidney transplant recipients are living in the US; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the FAVORIT (Folic Acid for Vascular Outcome Reduction In Transplantation) trial, we determined whether plasma levels of B-type natriuretic peptide (BNP) and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients
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